Use of anti-histaminics for acute reduction of elevated intracranial pressure

ABSTRACT

The invention concerns a novel histamine receptor antagonist and the use of an histamine receptor antagonist for the reduction of intracranial pressure (ICP), in particular for the prevention and treatment of elevated intracranial pressure and/or secondary ischaemida, in particular caused by brain injury, more in particular caused by traumatic (TBI) and non-traumatic brain injury. The novel compounds comprise compounds according to the general Formula (I) the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof and the N-oxide form thereof. In particular, the preferred compound is 3-[2-[4-(11,12-dihydro-6H-benzimidazo[2,1-b][3]benzazepin-6-yl)-2-(phenyl-methyl)-1-piperidinyl]ethyl]-2,10-dimethyl pyrimido[1,2-α]benzimidazol-4(10H)-one, the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof and the N-oxide form thereof. Also claimed is the novel use of commercially available histamine H1-and H2-receptor antagonists for the reduction of intracranial pressure (ICP).

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the national stage of Application No.PCT/EP02/13180, filed Nov. 22, 2002, which application claims priorityfrom EP 01204574.6 filed Nov. 23, 2001.

The invention concerns a novel histamine receptor antagonist and the useof an histamine receptor antagonist for the reduction of intracranialpressure (ICP), in particular for the prevention and treatment ofelevated intracranial pressure and/or secondary ischaemia, in particularcaused by brain injury, more in particular caused by traumatic (TBI) andnon-traumatic brain injury.

TBI is a significant problem in developed countries. In the USA eachyear about 500,000 head injuries are severe enough to requirehospitalisation. Mortality is high and approximately 80,000 of theseTBI-patients face a life-long debilitating loss of function, 5,000develop epilepsy and 2,000 live in a persistent vegetative state. TBI isthe leading cause of death and disability in young adults today at anestimated cost in 1989 of over $25 billion per year.

Primary irreversible damage after brain trauma includes hemorrhage,contusion, neuronal necrosis and diffuse axonal injury. This damage,together with possible cardiovascular and respiratory depression, caninduce acute secondary features including edema (vasogenic and/orcellular), secondary bleeding, alterations of cerebral blood volume(CBV), disturbed autoregulation of cerebral blood flow (CBF) andischaemia. Edema, bleeding and an increase of CBV will increase thetotal brain volume and consequently the intracranial pressure (ICP).This in turn can lead to further progression of ischaemia, infarction,and, in severe cases, herniation of the brain stem with possible acuterespiratory depression and death. Therapy in TBI should therefore bedirected to the interruption of the pathologic cascade and the reductionof the brain volume and ICP. Prevention of a life threatening secondaryincrease in ICP, which often occurs e.g. in the post-acute phase aftertrauma or after cardiac resuscitation, is also a target forpharmacological treatment.

At present, the clinical tools for ICP reduction are limited. Standardtreatment schedules include surgical drainage of the ventricles, bloodpressure management, mannitol infusion, hyperventilation and high dosebarbiturate therapy. Side effects of the non-surgical treatments includebrain ischaemia, rebound effects on ICP and an increased risk forbacterial infections and sepsis. Also, various compounds with differentmechanisms of actions (e.g. bradykinin antagonism, calcium antagonism,oxidative stress inhibition, glutamate receptor blockade andanti-epilepsy) have been tested in phase II and III clinical trials orare still under investigation (focus on outcome, not on ICP). Up to dateno compound has been approved for the acute treatment of intracranialpressure (K. K. Jain, Chapter 4: Neuroprotection in Acute Trauma,‘Neuroprotection in CNS Disorders: Commercial Opportunities’. A JainPharmaBiotech Report: 65-73, 2000). Obviously, there is a need forpharmaceuticals and/or therapies for the treatment of elevatedintracranial pressure (ICP) and/or secondary ischaemia, in particularcaused by brain injury, more in particular caused by traumatic braininjury (TBI).

SUMMARY OF THE INVENTION

The inventors have now found that substituted tetracyclic imidazolederivatives according to the general Formula (I) show histamine H1-and/or H2-receptor antagonist activity. Furthermore, the compounds havebeen shown to be particular useful for the reduction of intracranialpressure (ICP), in particular for the prevention and treatment ofelevated intracranial pressure and/or secondary ischaemia, in particularcaused by brain injury, more in particular caused by traumatic (TBI) andnon-traumatic brain injury.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Dose dependence of the ICP reducing effect of compound 2 duringa 10 min infusion period. X-axis : Dose (mg/kg/min) ; Y-axis : Change inICP as percentage of initial value.

FIG. 2. Dose dependence of the ICP reducing effect of Compound 2 duringthe 10 min post-treatment period following a 10 min infusion. X-axis :Dose (mg/kg/min) ; Y-axis : Change in ICP as percentage of initialvalue.

FIG. 3: Time course of ICP, MABP and CPP in rats during 3 intermittenttreatment periods of 10 min with respectively mannitol (FIG. 3-A)(dose:0.125 g/kg/min), Compound 2 (FIG. 3-B) (dose: 1 mg/kg/min) and solvent(FIG. 3-C)(10 % HP-beta-CD, pH 4). Treatment was started at 20 min aftersevere head injury (time=0) and was repeated at 30 min and 60 min. Thecurves connect the median value for the subsequent time points. Valuesare expressed as % of initial value.

FIG. 4: Time course of ICP, MABP and CPP in rabbits treated respectivelywith Compound 2 (FIG. 4-A)(dose: 2 mg/kg/min during 10 min) or solvent(FIG. 4-B) (2ml/min during 10 min). Treatment was started at 24 afterinduction of a cortical cold lesion (time=0). The curves connect themedian value for the subsequent time points. Values are expressed as %of initial value.

FIG. 5 : Time course of ICP, BP and CPP in rabbits (m=6) treated withPyrilamine (dose: 5 mg/kg/min during 10 min). The curves connect themedian value for the subsequent time points. Values are expressed as %of initial value.

DETAILED DESCRIPTION OF THE INVENTION

Furthermore, the inventors have found that compounds that antagonize thehistamine H1- and/or H12-receptors (commonly called anti-histaminics)are also usefull for the reduction of intracranial pressure (ICP), inparticular for the prevention and treatment of elevated intracranialpressure and/or secondary ischaemia, in particular caused by braininjury, more in particular caused by traumatic (TBI) and non-traumaticbrain injury.

Characteristical to all compounds is that they are able to acutelyreduce the intracranial pressure when administered to the bloodstream ofa mammal, in particular by intraveneous administration Advantageouslyand very important, said compounds reduce the ICP while having little orno effect on the blood pressure, in particular a blood pressure-loweringeffect, which is a most desired property of a potential drug. Hithertoo,histamine H1- and/or H2-receptor antagonists have not been developed forlowering the ICP, in particular for post-traumatic lowering of the ICP.Mohanty et al. in Journal of the Neurological Sciences 1989, 90:87-97observed that histamine played a role in the forming of traumaticalyinduced brain edema Increased brain water content and elevated plasmaand brain histamine levels were prevented by prior treatment with thehistamine H2-receptor antagonist cimetidine. However, meypyramine (anhistamine H1-receptor antagonist) failed to reduce the increased brainwater content and the histamine levels in the plasma and brain remainedhigh. The effect on the ICP, in particular the action of histamineantagonists after a rise of the ICP for acutely reducing an increasedICP was not researched nor was the effect on the blood pressure.

Without being restricted theretoo, it is the opinion of the inventorstat, in view of the fact that the histamine receptor antagonists showthe ability to reduce a normal ICP in the absence of brain edema and inview of the fact that the histamine receptor antagonists do not or onlymarginally influence the blood pressure, an effect attributed toperipheral vasodilatation, the mechanism of action is not one that actspurely on the reduction of brain edema nor via vasodilation, effectswhich are known in the prior art to occur for anti-histaminics.

Hence, the purpose of the present invention is to provide a substitutedtetracyclic imidazole derivatives for use as an histmine antagonist, inparticular as an histamine H1-antagonist, more in particular as anantagonist showing both histamine H1- and H2-antagonist activity,according to the general Formula (I)

the pharmaceutically acceptable acid or base addition salts thereof, thestereochemically isomeric forms thereof and the N-oxide form thereof,wherein:

-   m is 1 or 2;-   n is 0, 1 or 2;-   a, b, c independently are a single or a double bond;-   X is a covalent bond or a bivalent C₁₋₆alkanediyl radical wherein    one or more —CH₂— groups may be optionally replaced with —O—, —S—,    —CO—, or —NR⁷— wherein:    -   R⁷ is hydrogen, alkyl, Ar, Ar-alkyl, Het, Het-alkyl,        hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxyalkyloxyalkyl,        aminoalkyl, mono- or dialkylaminoalkyl, formyl,        alkylcarbonylaminoalkyl, alkylcarbonyloxyalkcyl,        alkyloxycarbonyl, alkyloxycarbonylalkyl, alkylaminocarbonyl,        allylaminocarbonylalkyl, hydroxyalkyloxyalkyl, aminocarbonyl,        aminocarbonylalkyl, alkyloxycarbonyl or        alkylcarbonyloxyalkyloxyalkyl;-   Y is a bivalent C₁₋₄alkanediyl or C₂₋₄ alkenediyl radical;-   Z is N, in which case a is a double bond and b is a single bond or    N—R⁷ in which case a is a single bond, b is a double bond and R⁷ is    defined as above;-   R¹, R² independently are hydrogen, hydroxy, alkyl, alkyloxy, Ar,    Ar-alkyl, di(Ar-)alkyl, Het or Het-alkyl;-   -A-B— independently is a bivalent radical of formula    -E-CR⁸═CR⁸—  (a-1);    —CR⁸═CR⁸-E-   (a-2);    —CR⁸═CR⁸—CR⁸═CR—  (a-3);    -   wherein        -   R⁸ each independently is hydrogen, halo, hydroxy, alkyl or            alkyloxy;        -   E is a bivalent radical of formula —O—, —S— or —NR⁷— wherein            R⁷ is defined as above;-   —C-D- independently is a bivalent radical of formula    —CR⁸═CR⁸—CR⁸═CR⁸—  (b-1);    —N═CR⁸—CR⁸═CR⁸—  (b-2)    —CR⁸═N—CR⁸═CR⁸—  (b-3)    —CR⁸═CR⁸—N═CR⁸—  (b-4);    —CR⁸═CR⁸—CR⁸═N—  (b-5)

wherein R⁸ is defined as above;

-   R³ is hydrogen, halo, hydroxy, alkyl, alkyloxy, Ar, Ar-alkyl,    di(Ar-)alkyl, Het or Het-alkyl;-   R⁴ is hydrogen, alkyl, amino, alkylamino, Ar-amino, Het-amino,    alkylcarbonylamino, Ar-carbonylamino, Het-carbonylamino,    alkylaminocarbonylamino, Ar-aminocarbonylamino,    Het-aminocarbonylamino, alkyloxyalkylamino, Ar-oxyalkylamino or    Het-oxyalkylamino;-   R⁵ is hydrogen or alkyl;    -   or R⁴ and R⁵ together may form a bivalent radical of Formula        -M—CR⁹═CR¹⁰—  (c-1);        —CR¹⁰═CR⁹-M-   (c-2);        -M—CR⁹R⁸—CR¹⁰R⁸—  (c-3);        —CR¹⁰R⁸—CR⁹R⁸-M-   (c-4);        —CR⁸═N—NR⁷—  (c-5);        —NR⁷—N═CR⁸—  (c-6);        —CR⁸═CR⁹—CR¹⁰═CR⁸—  (c-7);        —CR⁸R⁸—CR⁹R⁸—CR¹⁰R⁸-M-   (c-8);        -M—CR¹⁰R⁸—CR⁹R⁸—CR⁸R⁸—  (c-9);        —CR⁸R⁸—CR⁸═N—NR⁷—  (c-10);        —NR⁷—N═CR⁸—CR⁸R⁸—  (c-11);

wherein

-   -   R⁷ and R⁸ are defined as above;    -   R⁹, R¹⁰ independently are hydrogen, alkyl, halo, haloalkyl; or        R⁹ and R¹⁰ together may form a bivalent radical of formula        —CR⁸═CR⁸—CR⁸═CR⁸—; and    -   M is a bivalent radical of formula —CH₂—, —O—, —S— or —NR⁷—        wherein R⁷ is defined as above.

In the framework of this application, Ar is a homocycle selected fromthe group of naphthyl and phenyl, each optionally substituted with 1, 2or 3 substituents, each substituent independently selected from thegroup of hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino,alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl,aminocarbonyl and mono- or dialkylaminocarbonyl. Preferably, Ar is anaphthyl or phenyl, each optionally substituted with 1 substituent, eachsubstituent independently selected from the group of halo or alkyl.

In the framework of this application, Het is a monocyclic heterocycleselected from the group of pyrrolyl, pyrazolyl, imidazolyl, furanyl,thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl,pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycleselected from the group of quinolinyl, quinoxalinyl, indolyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzofuranyl and benzothienyl; each monocyclic andbicyclic heterocycle may optionally be substituted on a carbon atom withhalo, hydroxy, alkyl or alkyloxy. Preferably, Het is pyridinyl,pyrazinyl or indolyl.

In the framework of this application, alkyl is a straight or branchedsaturated hydrocarbon radical having from 1 to 6 carbon atoms ; or is acyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms; oris a a cyclic saturated hydrocarbon radical having from 3 to 6 carbonatoms attached to a straight or branched saturated hydrocarbon radicalhaving from 1 to 6 carbon atoms ; wherein each carbon atom can beoptionally substituted with halo, hydroxy, alkyloxy or oxo. Preferably,alkyl is methyl, ethyl or cyclohexylmethyl.

In the framework of this application, halo is a substituent selectedfrom the group of fluoro, chloro, bromo and iodo and haloalkyl is astraight or branched saturated hydrocarbon radical having from 1 to 6carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to6 carbon atoms, wherein one or more carbonatoms are substituted with oneor more halo-atoms. Preferably, halo is fluoro or chloro and preferably,haloalkyl is trifluoromethyl.

A preferred group of compounds are those compounds according to Formula(I), the pharmaceutically acceptable acid or base addition saltsthereof, the stereochemically isomeric forms thereof and the N-oxideform thereof, in which

-A-B— is a bivalent radical of formula (a-1) or (a-3), wherein E is abivalent radical of formula —O, —S— or —NR⁷— wherein R⁷ is hydrogen, R⁸is hydrogen, —C-D- is a bivalent radical of formula (b-1) or (b-2),wherein R⁸ is hydrogen and Y is a bivalent radical of formula —CH₂—,—CH₂—CH₂— or —CH═CH—.

Another group of preferred compounds of Formula (I) are those compoundsaccording to Formula (I), the pharmaceutically acceptable acid or baseaddition salts thereof, the stereochemically isomeric forms thereof andthe N-oxide form thereof, in which m and n are both 1.

Another group of preferred compounds of Formula (I) are those compoundsaccording to Formula (I), the pharmaceutically acceptable acid or baseaddition salts thereof, the stereochemically isomeric forms thereof andthe N-oxide form thereof, in which R¹ and R², each independently arehydrogen, alkyl, Ar-alkyl, Het or Het-alkyl.

Yet another group of preferred compounds of Formula (I) are thosecompounds according to Formula (I), the pharmaceutically acceptable acidor base addition salts thereof, the stereochemically isomeric formsthereof and the N-oxide form thereof, in which X is a bivalent radicalof formula —CH₂CH₂— or —CH₂CH₂CH₂—.

Yet another group of preferred compounds of Formula (I) are thosecompounds according to Formula (I), the pharmaceutically acceptable acidor base addition salts thereof, the stereochemically isomeric formsthereof and the N-oxide form thereof, in which R³ is hydrogen or alkyl,Z is N—R⁷ wherein R⁷ is hydrogen or alkyl, a is a single bond and b is adouble bond, and R⁴ and R⁵ together form a bivalent radical of Formula(c-1), (c-3), (c-5), (c-7), (c-8) or (c-10) wherein R⁷ and R⁸ arehydrogen.

Yet another group of preferred compounds of Formula (I) are thosecompounds according to Formula (I), the pharmaceutically acceptable acidor base addition salts thereof, the stereochemically isomeric formsthereof and the N-oxide form thereof, in which R³ is hydrogen or alkyl,Z is N—R⁷ wherein R⁷ is hydrogen or alkyl, a is a single bond and b is adouble bond, R⁴ and R⁵ together form a bivalent radical of Formula(c-1), (c-3), (c-5), (c-7), (c-8) or (c-10) wherein R⁷ and R⁸ arehydrogen and R⁹ and R¹⁰ together form a bivalent radical of formula—CR⁸═CR⁸—CR⁸═CR⁸— wherein R⁸ is hydrogen.

More specifically, the compound3-[2-[4-(11,12-dihydro-6H-benzimidazo[2,1-b][3]benzazepin-6-yl)-2-(phenylmethyl)-1-piperidinyl]ethyl]-2,10-dimethylpyrimido[1,2-α]benzimidazol-4(10H)-one, the pharmaceutically acceptableacid or base addition salts thereof, the stereochemically isomeric formsthereof and the N-oxide form thereof, are most preferred.

The pharmaceutically acceptable acid addition salts are defined tocomprise the therapeutically active non-toxic acid addition salt formswhich the compounds according to Formula (I) are able to form. Said acidaddition salts can be obtained by treating the base form of thecompounds according to Formula (I) with appropriate acids, for exampleinorganic acids, for example hydrohalic acid, in particular hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid;organic acids, for example acetic acid, hydroxyacetic acid, propanoicacid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinicacid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, cyclamic acid, salicyclic acid, p-aminosalicylicacid and pamoic acid.

The compounds according to Formula (I) containing acidic protons mayalso be converted into their therapeutically active non-toxic baseaddition salt forms by treatment with appropriate organic and inorganicbases. Appropriate base salts forms comprise, for example, the ammoniumsalts, the alkaline and earth alkaline metal salts, in particularlithium, sodium, potassium, magnesium and calcium salts, salts withorganic bases, e.g. the benzathine, N-methyl-D-glucamine, hybraminesalts, and salts with amino acids, for example arginine and lysine.

Conversely, said acid or base addition salt forms can be converted intothe free forms by treatment with an appropriate base or acid.

The term addition salt as used in the framework of this application alsocomprises the solvates which the compounds according to Formula (I) aswell as the salts thereof, are able to form. Such solvates are, forexample, hydrates and alcoholates.

Among the acid addition salts, the compound3-[2-[4-(11,12-dihydro-6H-benzimidazo[2,1-b][3]benzazepin-6-yl)-2-(phenylmethyl)-1-piperidinyl]ethyl]-2,10-dimethylpyrimido[1,2-α]benzimidazol-4(10H)-one (E)-2-butenedioate (2:3) hydrate(1:1) including all stereoisomeric forms thereof is the most preferredcompound.

Particularly preferred compounds are the (A)[(2α, 4β)(A)] enantiomer,the (B)[(2α,4β)(A)] enantiomer and a mixture thereof, of the compounds3-[2-[4-(11,12-dihydro-6H-benzimidazo[2,1-b][3]benrazepin-6-yl)-2-(phenylmethyl)-1-piperidinyl]ethyl]-2,10-dimethylpyrimido[1,2-a]benzimidazol-4(10H)-oneand3-[2-[4-(11,12-dihydro-6H-benzimidazo[2,1-b][3]benzazepin-6-yl)-2-(phenylmethyl)-1-piperidinyl]ethyl]-2,10-dimethylpyrimido[1,2-a]benzimidazol-4(10H)-one (E)-2-butenedioate (2:3) hydrate(1:1).

The N-oxide forms of the compounds according to Formula (I) are meant tocomprise those compounds of Formula (I) wherein one or several nitrogenatoms are oxidized to the so-called N-oxide, particularly those N-oxideswherein one or more nitrogens of the piperidinyl radical in Formula (1)are N-oxidized.

The term “stereochemically isomeric forms” as used herein defines allpossible isomeric forms which the compounds of Formula (I) may possess.Unless otherwise mentioned or indicated, the chemical designation ofcompounds denotes the mixture of all possible stereochemically isomericforms, said mixtures containing all diastereomers and enantiomers of thebasic molecular structure. More in particular, stereogenic centers mayhave the R— or S-configuration; substituents on bivalent cyclic(partially) saturated radicals may have either the cis- ortrans-configuration. Compounds encompassing double bonds can have an Eor Z-stereochemistry at said double bond. Stereochemically isomericforms of the compounds of Formula (I) are obviously intended to beembraced within the scope of this invention.

Following CAS nomenclature conventions, when two stereogenic centers ofknown absolute configuration are present in a molecule, an R or Sdescriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) tothe lowest-numbered chiral center, the reference center. Theconfiguration of the second stereogenic center is indicated usingrelative descriptors [R*,R*] or [R*,S*], where R* is always specified asthe reference center and [R*,R*] indicates centers with the samechirality and [R*,S*] indicates centers of unlike chirality. Forexample, if the lowest-numbered chiral center in the molecule has an Sconfiguration and the second center is R, the stereo descriptor would bespecified as S—[R*,S*]. If “α” and “β” are used: the position of thehighest priority substituent on the asymmetric carbon atom in the ringsystem having the lowest ring number, is arbitrarily always in the “α”position of the mean plane determined by the ring system. The positionof the highest priority substituent on the other asymmetric carbon atomin the ring system relative to the position of the highest prioritysubstituent on the reference atom is denominated “α”, if it is on thesame side of the mean plane determined by the ring system, or “β”, if itis on the other side of the mean plane determined by the ring system.

When the bond at c is a single bond, compounds of Formula (I) and someof the intermediate compounds have at least two stereogenic centers intheir structure. When R¹ is other than hydrogen, the monocyclic N-ringin Formula (I) has a further stereogenic center. This may lead to 8stereochemically different structures.

The compounds of Formula (I) as prepared in the processes describedbelow may be synthesized in the form of racemic mixtures of enantiomerswhich can be separated from one another following art-known resolutionprocedures. The racemic compounds of Formula (I) may be converted intothe corresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of Formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

Some of the compounds of Formula (I) may also exist in their tautomericform. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.For instance, compounds of Formula (I) wherein R⁵ is H may exist intheir corresponding tautomeric form.

The invention also comprises derivative compounds (usually called“pro-drugs”) of the pharmacologically-active compounds according to theinvention, which are degraded in vivo to yield the compounds accordingto the invention. Pro-drugs are usually (but not always) of lowerpotency at the target receptor than the compounds to which they aredegraded. Pro-drugs are particularly useful when the desired compoundhas chemical or physical properties that make its administrationdifficult or inefficient. For example, the desired compound may be onlypoorly soluble, it may be poorly transported across the mucosalepithelium, or it may have an undesirably short plasma half-life.Further discussion on pro-drugs may be found in Stella, V. J. et al.,“Prodrugs”, Drug Delivery Systems, 1985, pp.112-176, and Drugs, 1985,29,pp.455-473.

Pro-drugs forms of the pharmacologically-active compounds according tothe invention will generally be compounds according to Formula (I), thepharmaceutically acceptable acid or base addition salts thereof, thestereochemically isomeric forms thereof and the N-oxide form thereof,having an acid group which is esterified or amidated. Included in suchesterified acid groups are groups of the formula —COOR^(x), where R^(x)is a C₁₋₆alkyl, phenyl, benzyl or one of the following groups:

Amidated groups include groups of the formula —CONR^(y)R^(z), whereinR^(y) is H, C₁₋₆alkyl, phenyl or benzyl and R^(z) is —OH, H, C₁₋₆alkyl,phenyl or benzyl.

Compounds according to the invention having an amino group may bederivatised with a ketone or an aldehyde such as formaldehyde to form aMannich base. This base will hydrolyze with first order kinetics inaqueous solution.

The compounds according to Formula (1) can generally be prepared by asuccession of steps, each of which is known to the skilled person. Thepreparation of said compounds is disclosed in a co-pending application,which is included herein by reference.

Apart form their use for reducing the ICP, the compounds according toFormula (I) and derivatives thereof are also useful for the treatment ofother histamine H1- and H2-mediated diseases, in particular forimmunomodulation in a mammal, for the suppression of hypersensitivityand/or inflammatory reactions, for the treatment and prevention ofallergic diseases such as rhinitis, urticaria, asthma, anaphylaxis andthe like and for the treatment of gastrointestinal conditions such asulcers, dyspepsia, various reflux indications and the like. Theinvention is therefor also concerned with the use of an histaminereceptor antagonist according to Formula (I) and derivatives thereof forthe manufacture of a medicament for immunomodulation in a mammal, forthe suppression of hypersensitivity and/or inflammatory reactions andfor the treatment and prevention of allergic diseases andgastrointestinal conditions.

A further aspect of the invention is to provide for a new use forhistamine H1- and/or H2-receptor antagonists, in particular for acutelylowering the intracranial pressure (ICP), in particular an elevated ICP,more in particular a critically elevated ICP and/or preventing anelevated ICP and secondary ischaemia caused by brain injury. Mostadvantageously, the histamine H1- and/or H2-receptor antagonists do notor to a minimum extend lower or raise the blood pressure.

According to the invention, the histamine H1- and/or H2-receptorantagonists are either compounds and derivatives thereof according toFormula (I) or known histamine H1- and/or H2-receptor antagonists, beinga discrete and limited group of medications readily recognized in theart.

Hithertoo, histamine H1-receptor antagonists are commonly used forinmiunomodulation in a mammal and for the suppression ofhypersensitivity and/or inflammatory reactions. In particular, thehistamine H1-receptor antagonist is selected from the group ofacrivastine, alimemazine, antazoline, astemizole, azatadine, azelastine,brompheniramine, buclizine, carbinoxamine, carebastine, cetirizine,chlorcyclizine, chlorpheniramine, cinnarizine, clemastine, clemizole,clocinizine, clonidine, cyclizine, cyproheptadine,descarboethoxyloratidine, dexchlorpheniramine, dimenhydrinate,dimethindene, dimethothiazine, diphenhydramine, diphenylpyraline,doxylamine, ebastine, efletirizine, epinastine, fexofenadine,hydroxyzine, ketotifen, levocabastine, loratidine, meclizine,mequitazine, methdilazine, mianserin, mizolastine, niaprazine,noberastine, norastemizole, oxatomide, oxomemazine, phenbenzamine,pheniramine, picumast, promethazine, pyrilamine, temelastine,terfenadine, trimeprazine, tripelennamine and triprolidine, derivativesthereof and mixtures of any two or more of the foregoing.

Hithertoo, histamine H2-receptor antagonists are commonly used formamals suffering from certain gastrointestinal conditions such asulcers, dyspepsia, various reflux indications and the like. Inparticular, the histamine H2-receptor antagonist is selected from thegroup of ranitidine, cimetidine, famotidine, nizatidine, tiotidine,zolantidine, derivatives thereof and mixtures of any two or more of theforegoing.

Also, histamine receptor antagonists may exhibit both histaminic H1-and/or H2-receptor antagonist activity, such as ritanserine or thecompounds according to Formula (I), the pharmaceutically acceptable acidor base addition salts thereof, the stereochemically isomeric formsthereof and the N-oxide form thereof.

While all compounds show a marked depression of the ICP, the followingcompounds have been shown also to have no or little effect on thelowering of the blood pressure: ketotifen, chlorcyclizine, promethazine,pyrilamine, diphenylhydramine, chlorpheniramine and zolantadine.

In vitro studies can be used to evaluate the histamine antagonistactivity of the present compounds using appropriate receptor modellingstudies.

In vivo studies can be used to evaluate the biological activity of thepresent compounds. To this extent, a clinically relevant rat model fortraumatic brain injury (Closed Head Injury-model) was developed and usedto test the compounds according to the invention (K. Engelborghs et al.,Temporal changes in intracranial pressure in a modified experimentalmodel of closed head injury, J. Neurosurg. 89: 796-806, 1998; K. vanRossem et al., Brain oxygenation after experimental closed head injury,Adv. Exp. Med. Biol. 471: 209-215, 1999; K. Engelborghs et al., Impairedautoregulation of cerebral bloodflow in an experimental model oftraumatic brain injury, J. Neurotrauma, 17(8): 667-677, 2000). In onestudy intracranial hypertension was induced by a cortical cold lesion inrabbits.

The histamine receptor antagonist according to the invention, includingthe compounds according to Formula (I) and the currently known histamineH1-, H2- and H1/H2-receptor antagonists may be formulated into variouspharmaceutical forms for administration purposes. As appropriatecompositions there may be cited all compositions usually employed forsystemically administering drugs. To prepare the pharmaceuticalcompositions of this invention, an effective amount of the particularcompound, optionally in addition salt form, as the active ingredient iscombined in intimate admixture with a pharmaceutically acceptablecarrier, which carrier may take a wide variety of forms depending on theform of preparation desired for administration. These pharmaceuticalcompositions are desirable in unitary dosage form suitable, inparticular, for administration orally or by parenteral injection. Forexample, in preparing the compositions in oral dosage form, any of theusual pharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin, diluents,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations which are intendedto be converted, shortly before use, to liquid form preparations.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof. Most preferably, —for easeof quick administration—the aforementioned pharmaceutical composition isformulated as an injectable or perfusable solution or suspension.

The following examples illustrate the present invention without beinglimited thereto.

Experimental Part

Of some compounds the absolute stereochemical configuration of thestereogenic carbon atom(s) therein was not experimentally determined. Inthose cases the stereochemically isomeric form which was first isolatedis designated as “A” and the second as “B”, without further reference tothe actual stereochemical configuration. However, said “A” and “B”isomeric forms can be unambiguously characterized by a person skilled inthe art, using art-known methods such as, for example, X-raydiffraction.

For example, for the compound pyrimido[1,2-a]benzimidazol-4(10H)-one,3-[2-[4-(11,12-dihydro-6H-benzimidazo[2,1-b][3]benzazepin-6-yl)-2-(phenylmethyl)-1-piperidinyl]ethyl]-2,10-dimethyl,the 8 possible stereochemical isomeric forms are defined as follows:

CIS-forms (2α,4α)(A) (A)[(2α,4α)(A)] (B)[(2α,4α)(A)] (2α,4α)(B)(A)[(2α,4α)(B)] (B)[(2α,4α)(B)] TRANS-forms (2α,4β)(A) (A)[(2α,4β)(A)](B)[(2α,4β)(A)] (2α,4β)(B) (A)[(2α,4β)(B)] (B)[(2α,4β)(B)]

Hereinabove and hereinafter, “DMF” is defined as N,N-dimethylformamide,“DIPE” is defined as diisopropyl ether, “THF” is defined astetrahydrofurane, “MIBK” is defined as methyl isobutylketone, “DIPA” isdefined as diisopropylamine.

A. Preparation of the Intermediate Compounds

EXAMPLE A1

Use dry glassware. A mixture of(methoxymethyl)triphenylphosphoniumchloride (0.35 mol) in THF p.a.(mol.sieves) (2 l) was stirred at −50° C. under N₂ flow. BuLi, 2.5M/hexane(0.35 mol) was added dropwise and the mixture was stirred at −25° C. for30 min. A solution of 1,2-bis(phenylmethyl)-4-piperidinone (0.35 mol) inTHF was added dropwise at −25° C. The mixture was allowed to warm toroom temperature, then stirred at room temperature overnight anddecomposed with water. The organic solvent was evaporated. The aqueousconcentrate was extracted with CH₂Cl₂. The organic layer was separated,dried (MgSO₄), filtered and the solvent was evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH97.5/2.5). The pure fractions were collected and the solvent wasevaporated. Yielding: 121 g of4-(methoxymethylene)-1,2-bis(phenylmethyl)piperidine enantiomericmixture (intermediate 1) (100%).

A mixture of intermediate 1 (0.35 mol) in THF (500 ml) was stirred tillcomplete dissolution. H₂O (900 ml) and then HCl p.a. 38% (100 ml) wereadded. The mixture was stirred and refluxed for 3 hours. The organicsolvent was evaporated. The aqueous concentrate was alkalized with K₂CO₃and extracted with CH₂Cl₂. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH97/3). The pure fractions were collected and the solvent was evaporated.Yielding: 81 g of 1,2-bis(phenylmethyl)-4-piperidinecarboxaldehydeenantiomeric mixture (intermediate 2) (79%).

A mixture of DIPA (0.33 mol) in THF p.a. (previously dried on mol.sieves) (21) was stirred at −78° C. under N₂ flow. BuLi, 2.5M/hexane(0.276 mol) was added dropwise. The mixture was stirred at −78° C. for15 min. A solution of 1-(2-phenylethyl)-1H-benzimidazole (0.276 mol) inTHF was added dropwise. The mixture was stirred at −78° C. for 1 hour. Asolution of intermediate 2 (0.276 mol) in THF was added dropwise. Themixture was stirred at −78° C. for 1 hour, then allowed to warm to roomtemperature, stirred at room temperature overnight and then decomposedwith water. The organic solvent was evaporated. The aqueous concentratewas extracted with CH₂Cl₂. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH95/5 to 90/10). The pure fractions were collected and the solvent wasevaporated. Yielding: 113 g ofα-[1,2-bis(phenylmethyl)-4-piperidinyl]-1-(2-phenylethyl)-1H-benzimidazole-2-methanol(intermediate 3)(79%).

A mixture of intermediate 3 (0.22 mol) in trifluoromethanesulfonic acid(750 ml) was stirred at 110° C. for 7 hours. The mixture was cooled,poured out on ice, alkalized with NaOH 50% and extracted with CH₂Cl₂.The organic layer was separated, dried (MgSO₄), filtered and the solventwas evaporated. The residue was crystallized from CH₃CN. The mixture wasfiltered. The precipitate and the filtrate was purified separately bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 98.5/1.5 to95/5). Four pure fractions were collected and their solvents wereevaporated. The residues were crystallized from CH₃CN. The precipitateswere filtered off and dried. Yielding: 16 g of fraction 1[(2a,4β)(A)]-6-[1,2-bis(phenylmethyl)-4-piperidinyl]-11,12-dihydro-6H-benzimidazo[2,1-b][3]benzazepine(intermediate 4) (14.6%), 19.5 g of fraction 2[(2a,4β)(B)]-6-[1,2-bis(phenylmethyl)-4-piperidinyl]-11,12Aihydro-6H-benzimidazo[2,1-b][3]benzazepine (17.8%), 8.66 g fraction 3[(2α,4α)(A)]-6-[1,2-bisphenylmethyl-4-piperidinyl]-11,12-dihydro-6H-benzimidazo[2,1-b][3]benzazepine(7.9%) and 7.74 g of fraction 4[(2a,4α)(B)]-6-[1,2-bis(phenylmethyl)-4-piperidinyl]-11,12-dihydro-6H-benzimidazo[2,1-b][3]benzazepine(8.9%).

A mixture of intermediate 4 (0.0305 mol) in methanol (150 ml) washydrogenated at 50° C. overnight with Pd/C 10% (1 g) as a catalyst.After uptake of H₂ (1 equiv), the catalyst was filtered off and thefiltrate was evaporated. The residue was crystallized from CH₃CN. Theprecipitate was filtered off and dried. Yielding: 11.66 g of[(2a,4β)(A)]-11,12-dihydro-6-[2-(ghenylmethyl)4-piperidinyl]-6H-benzimidazo[2,1-b][3]benzazepine(intermediate 5) (94%).

EXAMPLE A2

Use dry glassware. A mixture of DIPA (0.22 mol) in THF p.a.(previouslydried on mol. sieves) (1400 ml) was stirred at −70° C. under N₂ flow.BuLi 2.5M (0.185 mol) was added dropwise and the mixture was stirred at−70° C. for 15 min. 1-(phenylmethyl)-1H-benzimidazole (0.185 mol)dissolved in THF was added dropwise at −70° C. and the mixture wasstirred at −70° C. for 1 hour. Intermediate 2 (0.185 mol) dissolved inTHF was added dropwise at −70° C. The mixture was stirred at −70° C. for1 hour, then brought slowly to room temperature, stirred at roomtemperature overnight and decomposed with H₂O. The organic solvent wasevaporated. The aqueous concentrate was extracted with CH₂Cl₂. Theorganic layer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH 95/5). The pure fractions werecollected and the solvent was evaporated. Yielding: 91 g of intermediate6 (98%).

A mixture of intermediate 6 (0.18 mol) in trifluoromethanesulfonic acid(700 ml) was stirred at 120° C. under N₂ flow for 18 hours. The mixturewas cooled, poured out on ice, alkalized with NaOH 50% and extractedwith CH₂Cl₂. The organic layer was separated, dried (MgSO₄), filteredand the solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/(CH₃OH/NH₃) 99/1). Thepure fractions were collected and the solvent was evaporated. Yielding:40 g of intermediate 7 (46%).

A mixture of intermediate 7 (0.081 mol) in methanol (200 ml) washydrogenated at 50° C. with Pd/C 10% (2 g) as a catalyst. After uptakeof H₂ (1 equiv), the catalyst was filtered off and the filtrate wasevaporated. This fraction was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/(CH₃OH/NH₃) 97/3). Two pure fractions werecollected and their solvents were evaporated. Yielding: Fraction 1 and12.5 g of intermediate 9 (cis isomers) (36%). Fraction 1 wascrystallized from CH₃CN. The precipitate was filtered off and dried.Yielding: 4.44 g of intermediate 8 (14%) ([(2α,4β)(A)]-racemate.

EXAMPLE A3

A mixture of DIPA (0.1 mol) in THF (100 ml) was stirred under N₂ flow.The mixture was cooled to −70° C. and BuLi, 2.5M/hexane (40 ml) wasadded portionwise. The temperature was allowed to reach −30° C., whilestirring for 10 min. The mixture was cooled to −70° C. A solution of1-(phenylethyl)-1H-benzimidazole (0.1 mol) in THF (50 ml) was addeddropwise at this temperature and the mixture was stirred for 2 h at −70°C. Ethyl 4-formyl-1-piperidinecarboxylate (0.1 mol) was added dropwiseand the mixture was stirred for 30 min at −70° C. The mixture wasallowed to reach room temperature and stirring was continued for 30 min.The mixture was decomposed with water, then evaporated. The residue wasstirred in water, and this mixture was extracted with CH₂Cl₂. Theorganic layer was separated, dried, filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH 98/2). The pure fractions werecollected and the solvent was evaporated. Yielding: 38 g of ethyl4-[hydroxy[1-(2-phenylethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidinecarboxylate(intermediate 10).

A mixture of intermediate 10 (0.011 mol) and MnO₂ (15 g) in CH₂Cl₂ (150ml) was stirred overnight at room temperature. MnO₂ was filtered offover dicalite. The reaction was performed a second time with identicalquantities. The mixture was stirred overnight. MnO₂ was filtered offover dicalite. The filtrate was evaporated. Yielding: 4.5 g ethyl4-[[1-(2-phenylethyl)-1H-benzimidazol-2-yl]carbonyl]-1-piperidinecarboxylate(intermediate 11).

A mixture of intermediate 11 (0.011 mol) and HBr, 48% aq. (25 ml) wasstirred for 10 h at 80° C. The solvent was evaporated. The residue wasstirred in boiling 2-propanol, cooled and the resulting precipitate wasfiltered off and dried. A sample (1 g) was recrystallized from ethanol.The crystals were filtered off and dried. Yielding: 0.5 g of[1-(2-phenylethyl)-1H-benzimidazol-2-yl](4-piperidinyl)methanonedihydrobromide (intermediate 12) (mp. 261.9° C.).

Trifluoromethanesulfonic acid (150 ml) was stirred under N₂ flow.Intermediate 12 (0.1 mol) was added portionwise and the resultingreaction mixture was stirred for 20 h at 100° C. (N₂ flow). The reactionmixture was cooled, poured out into ice (1 kg) and the resulting mixturewas neutralized with NaOH 50%, while stirring and cooling. This mixturewas extracted with CH₂Cl₂. Precipitation resulted. The organic layer wasseparated. The precipitate was filtered off and recrystallized fromCH₃CN. The crystals were filtered off and recrystallized again fromCH₃CN. The crystals were filtered off and dried. Yielding: 3.0 g of11,12-dihydro-6-(4-piperidinylidene)-6H-benzimidazo[2,1-b][3]benzazepine.trifluoromethanesulfonate(2:3). The separated organic liquor was combined with the mother layers,dried, filtered and the solvent was evaporated. The residue (37 g) wasdissolved in water/ethanol, alkalized with 50% NaOH and extracted withCH₂Cl₂. The separated organic layer was dried (MgSO₄), filtered and thesolvent was evaporated. The residue was stirred in 2-propanone/DIPE,then filtered off and dried. Yielding: 16.2 g of11,12-dihydro-6-(4-piperidinylidene)-6H-benzimidazo[2,1-b][3]benzazepine(intermediate 13) (mp. 180.3° C.).

EXAMPLE A4

Use dry glassware. A mixture of DIPA (1.1 mol) in THF p.a. (previouslydried on mol. sieves) (3000 ml) was stirred at −78° C. under N₂ flow.BuLi 1.5M in hexane (1.05 mol) was added dropwise at −70° C. and themixture was stirred at −70° C. for 20 min.1-(phenylethyl)-1H-benzimidazole (1 mol) dissolved in THF was addeddropwise at −78° C. and the mixture was stirred at −78° C. for 1 hour.4-ethyl 1-(1,1-dimethyl)1,4-piperidinedicarboxylate (1.1 mol) dissolvedin THF was added dropwise at −70° C. The mixture was stirred at −78° C.for 1 hour, then brought to room temperature, stirred at roomtemperature overnight and decomposed with H₂O. The organic solvent wasevaporated. The aqueous concentrate was extracted with CH₂Cl₂. Theorganic layer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue was crystallized from CH₃CN. The precipitate wasfiltered off and dried. Yielding: 350 g of intermediate 14 (81%).

Reaction under N₂ atmosphere. Methylmagnesium chloride (0.0165 mol; 8.2ml, 2.0 M/THF) was added dropwise to a solution of intermediate 14(0.0150 mol) in THF (90 ml), stirred at room temperature. The resultingreaction mixture was stirred for 2 hours. Water was added. The organicsolvent was evaporated and the aqueous concentrate was extracted withCH₂Cl₂. The separated organic layer was dried, filtered and the solventevaporated. The residue (6 g) was crystallized from CH₃CN. Theprecipitate was filtered off and dried. Yielding: 4.3 g of intermediate15 (64%).

A mixture of intermediate 15 (0.0076 mol) in trifluoromethanesulfonicacid (29 ml) was stirred for 48 hours at room temperature. The reactionmixture was poured out into water. This mixture was alkalized withK₂CO₃. The aqueous layer was extracted with CH₂Cl₂. The separatedorganic layer was dried, filtered and the solvent evaporated. Theresidue was purified by short open column chromatography over silica gel(eluent: CH₂Cl₂/(CH₃OH/NH₃) 90/10). The pure fractions were collectedand the solvent was evaporated. Yielding: 2 g of intermediate 16 (79%).

EXAMPLE A5

Reaction under N₂ atmosphere. Phenylmagnesium chloride (0.0440 mol) wasadded to a solution of intermediate 14 (0.0400 mol) in THF (200 ml),stirred at room temperature. The resulting reaction mixture was stirredfor one hour. Water was added. The organic solvent was evaporated andthe aqueous concentrate was extracted with is CH₂Cl₂. The separatedorganic layer was dried, filtered and the solvent evaporated. Thisresidue was combined with analogously obtained material and the whole(20 g) was crystallized from CH₃CN. The precipitate was filtered off anddried. Yielding: 20 g of intermediate 17 (98%).

A mixture of intermediate 17 (0.0360 mol) in trifluoromethanesulfonicacid (120 ml) was stirred for 24 hours, going from 0° C. to roomtemperature. The reaction mixture was poured out into water. Thismixture was alkalized with NaOH 50%, then extracted with CH₂Cl₂. Theseparated organic layer was dried, filtered and the solvent evaporated.The residue was crystallized from CH₃CN, filtered off, then purified byshort open column chromatography over silica gel (eluent:CH₂Cl₂/(CH₃OH/NH₃) 90/10). The pure fractions were collected and thesolvent was evaporated. Yielding: 11 g of intermediate 18 (78%).(mp.270.7° C.)

EXAMPLE A6

A mixture of 1-(2-phenylethenyl)-1H-benzimidazole (0.04 mol) in THF (100ml) was stirred under N₂ flow and cooled to −70° C. BuLi, 2.5 M/hexane(0.04 mol) was added dropwise at −70° C. and stiring was continued for30 min at −70° C. A solution of 4-ethyl1-(1,1-dimethylethyl)-1,4-piperidinedicarboxylate (0.04 mol) in THF wasadded dropwise and the mixture was stirred for 1 h at −70° C. Thetemperature was allowed to reach room temperature and the mixture wasdecomposed with water, then extracted with CH₂Cl₂. The separated organiclayer was dried (MgSO₄), filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃CN 97/3 upgrading to 94/6). Two fractions were collected andthe solvent was evaporated. The second fraction's residue wascrystallized from DIPE/CH₃CN. The crystals were filtered off and dried.Yielding: 7.0 g of (1,1-dimethylethyl)(Z)-4-[[1-(2-phenylethenyl)-1H-benzimidazol-2-yl]carbonyl]-1-piperidinecarboxylate(41%) (intermediate 19). (mp. 155.8° C.)

A mixture of intermediate 19 (0.043 mol) in trifluoroacetic acid (130ml) was stirred for ½ hour at room temperature. The reaction mixture waspoured out into diethylether. The precipitate was filtered off, washedwith diethylether and dried. Yielding: 18 g of(Z)-[1-(2-phenylethenyl)-1H-benzimidazol-2-yl](4-piperidinyl)methanonetrifluoroacetate (1:1) (intermediate 20) (94.0%). (mp. 202.2° C.)

A mixture of intermediate 20 (0.0276 mol), AlCl₃ (0.187 mol) and NaCl(0.187 mol) was stirred for 1 hour at 150° C. (melt). The reactionmixture was decomposed in a mixture of ice, water and NaOH 50%. Themixture was extracted with dichloromethane and the organic layer wasseparated, dried, filtered and evaporated. The residue (4.3 g) waspurified on a glass filter over silica gel (eluent: CH₂Cl₂/(CH₃OH/NH₃)90/10). The pure fractions were collected and the solvent wasevaporated. The residue was converted into the (E)-2-butenedioic acidsalt (2:3) in ethanol. The salt was filtered off and dried. Yielding:1.8 g of6-(4-piperidinylidene)-6H-benzimidazo[2,1-b][3]benzazepine.(E)-2-butenedioate(2:3) (13.4%) (intermediate 21). (mp. 229.4° C.)

EXAMPLE A7

A mixture of 2-amine-1H-benzimidazole (0.04 mol),3-acetyldihydro-2(3H)-furanone (0.53 mol) and 4-methylbenzenesulfonicacid (4 g) in xylene (930 ml) was stirred and refluxed overnight andthen cooled. The precipitate was filtered off and stirred in H₂O (200ml), Na₂CO₃ (5 g) and CH₂Cl₂ (500 ml). The precipitate was filtered off,boiled in CH₃OH, filtered off and dried. Yielding: 47.4 g of3-(2-hydroxyethyl)-2-methyl-pyrimido[1,2-a]benzimidazol-4(10H)-one(intermediate 22).

A mixture of intermediate 22 (0.025 mol) and K₂CO₃ p.a. (0.03 mol) inDMF (70 ml) was stirred at 50° C. Methyliodide (0.03 mol) was addeddropwise. The mixture was stirred at 50° C. for 4 hours and cooled. Thesolvent was evaporated. The residue was boiled in CH₃OH. The precipitatewas filtered off and dried. The residue was purified by HPLC over silicagel (eluent: CH₂Cl₂/(CH₃OH/NH₃) 97/3). Two pure fractions were collectedand their solvents were evaporated. Yielding: 2.08 g of3-(2-hydroxyethyl)-2,10-dimethyl-pyrimido[1,2-a]benzimidazol-4(10H)-one(intermediate 23).

A mixture of intermediate 23 (0.02 mol) and SOCl₂ (0.06 mol) in CHCl₃(50 ml) was stirred and refluxed for 4 hours and then cooled. H₂O wasadded. The mixture was alkalized with K₂CO₃ and separated into itslayers. The aqueous layer was extracted with CH₂Cl₂. The combinedorganic layer was dried (MgSO₄), filtered and the solvent wasevaporated. The residue was crystallized from CH₃CN. The precipitate wasfiltered off and dried. Yielding: 3.44 g of intermediate 24.

B. Preparation of the Final Compounds

EXAMPLE B1

TABLE 1

Co. Phys. data and nr. Ex. nr. R¹ R X stereochemistry 9 B1 2-benzyl

—CH₂—CH₂— [(2a,4a)(B)] 10 B1 2-benzyl

—CH₂—CH₂— [(2a,4a)(B)] 11 B1 2-benzyl

—CH₂—CH₂— [(2a,4a)(B)]; .H₂O(1:2) 12 B1 2-benzyl

—CH₂—CH₂— [(2a,4a)(B)] 13 B1 2-benzyl

—CH₂—CH₂— [(2a,4μ)(B)] 14 B1 H

—CH₂—CH₂— 15 B1 2-benzyl

—CH₂—CH₂— [(2a,4β)(A)]; (E)- 2-butenedioate(2:3) 16 B1 2-benzyl

—CH₂—CH₂— [A(2a,4α)(B)] 17 B1 2-benzyl

—CH₂—CH₂— [B(2a,4α)(B)] 18 B1 2-methyl cyclohexy

—CH₂—CH₂— 19 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)] 20 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)] 21 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)] 22 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)] 23 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)] 24 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)] 25 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)] 26 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)]; .H₂O(1:1) 27 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)] 28 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)] 29 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)] 30 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(A)] 31 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)] 32 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)] 33 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)] 34 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)]; .H₂O(1:1) 35 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)]; .H₂O(1:1) 36 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)]; .H₂O(1:1) 37 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)] 38 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)]; .H₂O(1:1) 39 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)]; .H₂O(1:1) 40 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)] 41 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)] 42 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)] 43 B1 2-benzyl

(CH₂)₂—C(═O) [(2a,4α)(A)] 44 B1 2-benzyl

—CH₂—CH₂— [A(2a,4α)(A)] 45 B1 2-benzyl

—CH₂—CH₂— [B(2a,4β)(A)] 46 B1 2-benzyl

—CH₂—CH₂— [A(2a,4β)(B)]; Tri- fluoroacetate(1:1) 47 B1 2-benzyl

—CH₂—CH₂— [B(2a,4β)(B)]; Tri- fluoroacetate(1:1) 48 B1 2-benzyl

—CH₂—CH₂— [(2a,4β)(A)] 49 B1 2-benzyl

—CH₂—CH₂— [(2a,4β)(A)]; (−)-[S(R*,R*)]- 2,3-dihydroxy butanedioate(1:2)50 B1 2-benzyl

—CH₂—CH₂— [(2a,4β)(A)]; .HCl(1:3).H2O (1:2) 51 B1 2-benzyl

CH₂—CH₂—CH [(2a,4β)(A)]; .H2O(1:2) 52 B1 2-benzyl

—CH₂—CH₂— [(2a,4β)(A)] 53 B1 2-benzyl

—CH₂—CH₂— [(2a,4β)(A)] 54 B1 2-benzyl

—CH₂—CH₂— [(2a,4β)(A)]; (E)- 2-butenedioate(1:1) 55 B1 2-benzyl

—CH₂—CH₂— [(2a,4β)(A)]; (E)- 2-butenedioate (1:1).H₂O(1:2) 2 B1 2-benzyl

—CH₂—CH₂— [A(2a,4β)(A)]; (E)- 2-butenedioate (2:3).H₂O(1:1) 1 B12-benzyl

—CH₂—CH₂— [B(2a,4β)(A)]; (E)- 2-butenedioate (2:3).H₂O(1:1) 56 B12-benzyl

CH₂—CH₂—CH [(2a,4α)(B)] 57 B1 2-benzyl

—CH₂—CH₂— [A(2a,4α)(A)] 58 B1 2-benzyl

—CH₂—CH₂— [B(2a,4α)(A)] 59 B1 2-benzyl

[(2a,4α)(A)] 60 B1 2-benzyl

—CH₂—CH₂— [(2a,4α)(B)] 109 B1 2-benzyl

—CH₂— [(2α,4α)(B)] 152 B1 H

—CH₂—CH₂— 153 B1 H

CH₂—CH₂—CH (E)-2- Butenedioate (2:5)

TABLE 2

Comp. nr Ex. nr. R¹

Phys. data and stereochemistry 61 B2 H —CH═CH—S— 62 B2 H —CH₂—CH₂—S— 63B2 H —CH₂—CH₂—CH₂—S— 64 B2 H —CH═CH—CH═CH— 65 B2 H —CH₂—C(CH₃)═N—N(CH₃)—66 B2 H —C(CH₃)═N—N(CH₃)— 67 B2 H —CH═CH—N(CH₃)— 68 B2 H —O—C(CH₃)═CH—69 B2 H —CH═C(CH₃)—N(CH₃)— 70 B2 H —CH═C(CH₃)—CHCH— 71 B2 H—C(CH₃)═CH—S— 72 B2 H —CH═CH—CH═C(CH₃)— 73 B2 2-benzyl —CH═CH—S—[(2α,4β)(B)] 74 B2 2-benzyl —CH═CH—S— [(2α,4α)(A)] 75 B2 2-benzyl—CH═CH—S— [(2α,4α)(B)] 76 B2 2-benzyl —CH═CH—S— [(2α,4β)(A)]; (E)-2-butenedioate (1:2)ethanolate(1:1) 77 B2

—CH═CH—S— [(2α,4α)(A)] 78 B2

—CH═CH—S— [(2α,4β)(B)] 79 B2

—CH═CH—S— [(2α,4α)(B)] 80 B2 2-benzyl —CH═CH—CH═CH— [(2α,4α)(B)] 81 B22-benzyl —CH═CH—CH═CH— [(2α,4β)(A)] 82 B2 2-benzyl —CH═CH—CH═CH—[(2α,4β)(B)] 83 B2 2-methylnaphthyl —CH═CH—S— [(2α,4β)(A)] 84 B22-methylnaphthyl —CH═CH—S— [(2α,4β)(B)] 85 B2 2-methylnaphthyl —CH═CH—S—[(2α,4α)(B)] 86 B2 2-methylnaphthyl —CH═CH—S— [(2α,4α)(A)]; .H₂O(1:1)ethanolate(1:1) 87 B2 3-methyl —CH═CH—S— A-trans 88 B2 3-methyl—CH═CH—S— B-trans 89 B2 3-methyl —CH═CH—CH═CH— [(3α,4β)(B)] 90 B23-methyl-(4- —CH═CH—S— [(2α,4β)(A)] fluorophenyl) 91 B2 3-methyl-(4-—CH═CH—S— [(2α,4β)(B)] fluorophenyl) 92 B2 3-methyl-(4- —CH═CH—S—[(2α,4α)(A)] fluorophenyl) 93 B2 3-methyl-(4- —CH═CH—S— [(2α,4α)(B)]fluorophenyl) 94 B2 3-methyl —CH═CH—CH═CH— [(3α,4β)(A)] 95 B2 2-benzyl—CH═C(CH₃)—N(CH₃)— [(2α,4α)(B)] 96 B2 2-benzyl —CH═CH—N(CH₃)—[(2α,4α)(B)] 97 B2 2-benzyl —CH═CH—CH═C(CH₃)— [(2α,4α)(B)] 98 B22-benzyl —CH₂—CH₂—S— [(2α,4α)(B)] 99 B2 2-benzyl —CH₂—C(CH₃)═N—N(CH₃)—[(2α,4α)(B)] 100 B2 2-benzyl —CH═C(CH₃)—CH═CH— [(2α,4α)(B)] 101 B22-benzyl —C(CH₃)═CH—C(CH₃)═CH— [(2α,4α)(B)] 102 B2 2-benzyl—CH═C(Cl)—CH═C(Cl)— [(2α,4α)(B)] 103 B2 2-benzyl —CH═C(CF₃)—CH═C(Cl)—[(2α,4α)(B)] 104 B2 4-methyl —CH═CH—S— 105 B2 2- —CH═CH—CH═CH—methylcyclohexyl 106 B2 2-benzyl —CH═CH—S— [A(2α,4α)(B)] 107 B2 2-benzyl—CH═CH—S— [B(2α,4α)(B)] 108 B2 2- —CH═CH—S— methylcyclohexyl

TABLE 3

Comp. nr Ex. nr. R²

Phys. data and stereo- chemistry  6 B4 a) —Me —CH═CH—CH═CH— hydrate(1:1) 110 B4 a) —Me —CH═CH—S— 111 B4 a) —CH₂—Phe —CH═CH—CH—CH— 112 B5 b)—CH₂—Phe —CH═CH—CH═CH—  7 B5 b) —CH₂—Phe —CH═CH—S— 113 B4 a) —Phe—CH═CH—S—

TABLE 4

Co. nr. Ex. nr.

Phys. data and stereochemistry 114 B1 —CH═CH—CH═CH— —CH═CH—S——CH═CH—CH═CH— H₂O(1:1) (E)-2- butenedioate(1:1) 115 B1 —CH═CH—S——CH═CH—S— —CH═CH—CH═CH— H₂O(2:1) (E)-2- butenedioate(2:3) 116 B1—CH═CH—CH═CH— —CH═CH—CH═CH— —N═CH—CH═CH— 117 B1 —CH═CH—S— —CH═CH—CH═CH——N═CH—CH═CH— 118 B1 —CH═CH—S— —CH═CH—N(CH₃)— —N═CH—CH═CH—

TABLE 5

Co. nr. Ex. nr. R¹ R²

Phys. data and stereochemistry 119 B2 2-benzyl H —CH═CH—S— cis 3 B22-benzyl H —CH═CH—S— [(2a,4β)(B)] 4 B2 2-benzyl H —CH═CH—S— trans 120 B22-benzyl H —CH═CH—CH═CH— [(2a,4β)(B)] 121 B2 2-benzyl H —CH═CH—CH═CH—[(2a,4β)(A)] 122 B2 H H —CH₂—CH₂—CH₂—CH₂— 123 B2 H H —CH₂—CH₂—CH₂—S— 124B2 H H —CH═CH—CH═CH— 125 B2 H H —CH₂—CH₂—S— 126 B2 H H —C(CH₃)═CH—S— 127B2 H H —CH═C(CH₃)—CH═CH— 128 B2 H H —CH═CH—CH═C(CH₃)— 129 B2 H H—CH₂—C(CH₃)═N—N(CH₃)— 130 B2 H H —CH═CH—N(CH₃)— 131 B2 H H—CH═C(CH₃)—N(CH₃)— 132 B2 H H —O—C(CH₃)═CH— (E)-2-butenedioate (1:2) 133B2 H H —C(CH₃)═N—N(CH₃)— .H₂O(1:1) 134 B2 2-benzyl H —CH═CH—CH═CH—[(2α,4α)(B)] 135 B2 2-benzyl H —CH═CH—CH═CH— [(2α,4α)(A)] 136 B2 H H—CH═CH—S— .ethanedioate(2:5) .H₂O (2:1)

TABLE 6

Co. nr. Ex. nr.

Phys. data and stereochemistry  5 B3 —CH—CH—S— 137 B3 —CH₂—CH₂—S— 138 B3—CH₂—CH₂—CH₂—S— 139 B3 —CH═CH—CH═CH—

TABLE 7

Phys. data and Co. nr. Ex. nr.

stereochemistry 140 B6 —CH═CH—CH═CH— 141 B6 —CH₂—CH₂—CH₂—S—  8 B6—CH═CH—S— 142 B6 —CH₂—CH₂—S

TABLE 8

Phys. data and Co. nr Ex. nr. Y R¹ R⁴ R⁵ stereochemistry 143 B2—CH₂—CH₂— H

—CH₃ 144 B1 —CH₂—CH₂— H

—CH₃ 145 B1 —CH₂—CH₂— H

—CH₃ .H₂O(1:1) 146 B1 —CH₂—CH₂— H

—CH₃ 150 B1 —CH₂—CH₂— 2-benzyl —NH₂ —CH₃ [(2α,4α)(B)] 147 B2 —CH₂— H—NH₂ —CH₃ (Z)-2-Butenedioate (1:3).H₂O(1:1) 148 B2 —CH₂— H

—CH₃ 149 B2 —CH₂— H

—CH₃ 151 B2 —CH₂— H

—CH₃ .HCl(1:3).H₂O(1:2) .2-propanolate(2:1)C. Pharmacological ExamplesC1. In Vitro Determination of the Histaminic H1-and H2-AntagonistActivity.

Radioligand receptor binding studies were performed in vitro forradioligand binding of the selected compounds using a preparation of atissue which was enriched in a particular receptor, i.e. the histamineH1- or H2-receptor. For the histamine H1-receptor, the tissue used wereCHO-cells, permanently transfected with the human histamine H1-receptor.Only diphenhydramine was tested against guinea pig cells from thecerebral cortex . Competitive inhibition of [³H] Pyrilamine by thetested compounds was conducted by incubating a low (nM) concentration ofthe radioligand with a small sample of the tissue preparation (0.2-5 ml;1-5 mg tissue) in a buffered medium and various concentrations of thecompounds, dissolved in DMSO, spanning at least 4 orders of magnitutudearound the pIC₅₀ value, derived from the inhibition curve. Thehistaminic H2-antagonist activity was tested in much the same way as thehistaminic H1-antagonist activity, using guinea pig striatum cells and[¹²⁵I]APT as the radioligand in a concentration of 0.1 nM. Incubationwas done during 150 min at 22° C.

All compounds according to our invention showed a pIC₅₀ value of 5 ormore for histaminic H1-antagonist activity. Several compounds showed apIC₅₀ value of 6 or more for histaminic H1-antagonist activity. Thesecompounds are listed in Table 9. Furthermore is observed that acommercially available typical histamine H1-antagonist (diphenhydramine)exhibits only a slightly higher histaminic H1-antagonist activity as thebulk of the compounds according to our invention. Furthermore is shownthat the commercially available H2-antagonists (ranitidine andcimetidine) exhibit histamine H2-activities in the range of the(moderately high) H2-activities of the compounds according to ourinvention. A selection of the compounds in Table 9, includingcommercially available compounds, was also tested in in vivo experimentsfor their ability to reduce ICP.

TABLE 9 Results of the histamine H1- and H2-antagonist activity receptormodel screening. H1-antagonist H2-antagonist activity activity Comp. nr(pIC₅₀) (pIC₅₀)  14 7.6  94 7.0 104 7.0  46 6.9 110 6.9  1 (also testedin vivo) 6.7 6.0  6 6.7  23 6.7  78 6.7  81 6.7  82 6.7  50 6.6  55 6.6 87 6.6  12 6.5  13 6.5  15 (also tested in vivo) 6.5  45 (also testedin vivo) 6.5  48 6.5  49 6.5  53 6.5  54 6.5  83 6.5  88 6.5  20 6.4  32(also tested in vivo) 6.4  47 (also tested in vivo) 6.4  57 6.4  58 6.4105 6.4  29 6.3  51 6.3  84 6.3  17 (also tested in vivo) 6.2  27 6.2 37 6.2  2 (also tested in vivo) 6.1  30 (also tested in vivo) 6.1  356.1  56 6.1  89 6.1  90 6.1  9 (also tested in vivo) 6.0  31 6.0  41 6.0 44 (also tested in vivo) 6.0 102 6.0 Ranitidine — 5.5 (also tested invivo) Cimetidine — 5.9 Diphenhydramine 7.2 — (also tested in vivo)C.2. In Vivo PharmacologyClosed Head Injury (CHI) Model

A clinically relevant rat model for traumatic brain injury was used totest the compounds according to the invention and the commerciallyavailable compounds. This model mimics several clinical features oftraumatic brain injury, such as increased ICP, decreased cerebralperfusion pressure, morphologic alterations including diffuse axonalinjury, neuronal necrosis and contusion, impairment of autoregulation ofcerebral blood flow and reduction of brain oxygenation and was appliedfor screening drugs with ICP-lowering effects. Trauma was induced inintubated, isoflurane anesthetized (1.5% isoflurane in a mixture of 30%O₂ and 70% N₂O) Sprague-Dawley rats (380-400 g) stereotaxicallypositioned on a table mounted on 4 springs. A 400 g steel cylinder,protected with a 9 mm diameter silicon disc, was dropped on theunprotected skull from a height of either 70 cm or 50 cm (respectively‘severe’ and ‘moderate’ head injury). The impact area was centeredbetween bregma and lamda. ICP was recorded using a Codman microsensorprobe inserted in the parietal cortex. In both severe and moderate headinjuries the ICP increased immediately after trauma and remainedelevated for several days. The severe head injury mode was used for theevaluation of pharmacological effects immediately after trauma(screening procedure). When survival and recovery from anesthesia wasenvisaged, the moderate head injury mode was applied. In pharmacologicalstudies, animals with a pathological ICP between 12.5 and 35 mm Hg wereincluded. The changes in ICP, mean arterial blood pressure (MABP) andcerebral perfusion pressure CPP (=MABP—CPP) were expressed as percentageof the initial value at onset of the treatment.

Screening Procedure for the Compounds According to the Invention

On a weekly base, 4 treated groups of 3 rats were compared with 3 salinetreated animals. Since conventional statistical methods require a largeramount of animals, a sequential procedure was used. Sequential methodsoperate in different stages. At each stage, a group of animals wasselected as homogeneous as possible. Animals were randomly allocated toeither drugs or saline. The procedure allowed to make the decision ofrejecting the drug, accepting the drug as active or to continue with anew group of animals in a next stage. Given the biological relevantlevel of activity that must be detected, the expected fraction of falsepositive and negative results was known and fixed. A sequentialtwo-sample grouped rank test was used. A three stage sequential designwith a relatively small number of animals at each stage showed to beoptimal. Despite the variability in the individual data, the procedureconsistently accepted reference treatments such as mannitol as active,while controls were rejected. Clinically relevant i.v. doses of mannitol(3 g over 45 min) consistently reduced the ICP (mean reduction about20%).

TABLE 10 Results of the screening procedure. Treatment⁽¹⁾ Delta %⁽²⁾Decision⁽³⁾ Compound 9 −12.4 active Compound 15 −23.3 active Compound 17−8.9 active Compound 30 −9.3 active Compound 32 −13.9 active Compound 44−14.8 active Compound 45 −13.1 active Compound 47 −12.0 active CD10% 5.1not active CD10% + 3H2T 10.0 not active CD20% 19.1 not active CD20% +HCl 2.4 not active Mannitol¹ −21.7 active Mannitol² −22.1 activeMannitol³ −13.0 active Mannitol⁴ −19.3 active Mannitol⁵ −19.9 active⁽¹⁾Experimental compounds administered as a bolus of 1 mg/kg given in 1min, followed by an infusion of 0.5 mg/kg/min for 44 min; solventsadministered as a 0.4 ml bolus in 1 min followed by an infusion of 0.2ml/min for 44 min; mannitol given as an infusion of 67 mg/kg/min for 45min. ⁽²⁾Delta %: average change of the relative ICP from baseline overthe treatment period. ⁽³⁾Decision: based upon sequential statisticalevaluation. CD = hydroxypropyl-β-cyclodextrin solvent H2T = tartaricacid solvent Mannitol¹⁻⁵: Mannitol was evaluated 5 times in separatetests (positive controls). The result of each test is mentioned.Further Studies

Table 11 shows the changes in some relevant physiological variablesrecorded during treatment after severe CHI in rats. Treatment wasstarted at 20 min after severe head injury and involved administering adose of 0.5 mg/kg/min during 10 minutes, followed by 0.1 mg/kg/minduring 50 min.

TABLE 11 Changes in relevant physiological variables during treatmentafter severe CHI in rats. Racemate (comp. 1 and Solvent Compound 2Compound 1 comp. 2) (n = 10) (n = 10) (n = 10) (n = 10) ICP (%)   1.6(−9.4; 11.1) −15.3 (−20.0; −9.5)* −15.4 (−22.6; −11.5)* −19.1 (−24.9;−10.8)* MABP (%) −1.2 (−2.7; 3.7)   18.8 (−2.0; 31.0)*  −3.6 (−11.9;−1.5)    0.6 (−5.1; 8.5) CPP (%) −1.3 (−8.0; 5.8)   24.2 (0.9; 43.6)* −1.9 (−8.9; 0.4)    7.5 (−2.4; 15.5) ETCO₂ (%)   8.0 (−1.2; 12.9)  −4.4(−8.9; 2.3)*    2.2 (−0.8; 8.4)    2.4 (−7.8; 3.8) Heart rate(%) −2.7(−5.4; 3.9)  −9.6 (−21.8; 0.7)  −4.1 (−11.4; 1.9)    5.6 (−11.7; 0.4)Resp. rate(%)   3.6 (−4.3; 11.8)    6.6 (−1.3; 14.6)    5.3 (−3.3; 13.6)   9.6 (3.0; 14.8) Average change over the entire treatment period,expressed as % change of initial value. Values are medians (95% C.I.).*= Significantly different from solvent group (p < 0.05, Dunnett's test)Solvent: 10% hydroxypropyl-beta-cyclodextrine, tartaric acid, NaOH andmannitol in pyrogen free water; pH = 4; osmolarity 312-314 mOsm/kg;compound concentration 2 mg/ml. Compound:pyrimido[1,2-a]benzimidazol-4(10H)-one, 3-[2-[4-(11,12-dihydro-6H-benzimidazo[2,1-b][3]benzazepin-6-yl)-2-(phenylmethyl)-1-piperidinyl]ethyl]-2,10-dimethyl(E)-2-butenedioate (2:3) hydrate (1:1) Compound 1: (B)[(2α, 4β)(A)]Compound 2: (A)[(2α, 4β)(A)] Racemate (comp. 1 and comp. 2): (2α,4β)(A), i.e. the racemic mixture of Compound 1 and Compound 2 ICP:Intracranial pressure MABP: Mean arterial blood pressure CPP: Cerebralperfusion pressure ETCO₂: End tidal CO₂

The significant effect of compound 2 on MABP is much less pronouncedwhen the compound is given at a continuous infusion of 0.1 mg/kg.min. Inthis case a blood pressure peak is not present and increases in MABPlarger than 20% are not observed (median MABP increase at the end of theinfusion is 9%, n=6). The maximal reduction of ICP at this dose iscomparable to the one observed when the infusion is preceded by the‘loading dose’ of 5 mg/kg over 10 min, but the time required to obtainthis effect is longer (median: 30 min).

Effect of Ranitidine and Dinhenhydramine on the ICP

Ranitidine was infused for 6 min at a dose of 2 mg/kg/min in the ratCHI-model after inflicting severe head injury. Solvent (NaCl+H2T) wasgiven at the same rate. In each group, 6 rats were treated. Ranitidinewas observed to yield a statistically significant larger reduction inICP than in the solvent-treated group (7.7% versus 0.5% reduction, whichwas significant at p=0.013). The percentage of reduction are calculatedas % change of the ICP recorded at the onset of the treatment and at theend of the infusion. No significant change in blood pressure wasobserved.

Diphenhydramine was infused for 10 min at a dose of 1 mg/kg/min in therat CHI-model after inflicting severe head injury. Three rats weretreated. Diphenhydramine was observed to yield a 34% reduction in ICPwithout any significant effect on the blood pressure.

Comparative Experiments with Agonists.

For comparison, two commercially available H2-agonists (dimaprit andimpromidine) were also tested by infusion into non-traumatized rats,using a dose of 0.5 mg/kg/min for 10 minutes for dimaprit and increasingdoses up to 3.75 mg/kg/hour for impromidine. No effects were observed.When dimaprit was dosed at the high dose of 2 mg/kg/min for 10 minutes,and impromidine was doses as a bolus of 0.5 mg/kg blood pressure and ICPwere observed to drop, but recovered after the treatment.

It was therefor concluded that histamine H1-and/or H2-receptorantagonists exhibited the effect of lowering the ICP and having in themeantime hardly any significant effect on the blood pressure.

Experiments with Commercially Available H1- and H2-Antaponists

A number of commercially available H1- and H2-antagonists was infusedfor 10 min at a dose of 0.5 mg/kg/min in the rat CHI-model afterinflicting severe head injury. Solvent (NaCl+H2T) was given at the samerate. In each group, 6 rats were treated. The results of the behavior ofthe ICP and BP in the first 15 minutes are summarized in Table 12.

TABLE 12 Effect of commercially available H1- and H2-antagonists. Effecton Compound Effect on ICP blood pressure solvent 0 0 Cyclodextrine − +Alimemazine − − Antazoline −− −− Brompheniramine − −− Chlorcyclizine − 0Chlorpheniramine − + Clemastine − −− Clemizole − − Cyproheptadine −− −−Dimethindene − + Diphenhydramine −− 0 Diphenylpyraline − —/0 Hydroxyzine− 0 Ketotifen −− 0 Loratidine − + Niaprazine −− −− Oxatomide − −Pheniramine −− − Promethazine − + Pyrilamine (see FIG. 5) −− 0Ritanserine −− − Tiotidine −− —/0 Zolantidine − 0 0: no effect; −:decrease; −−: strong decrease; +: increaseDose Response for Compound 1

Results of a blinded, completely randomized study of the effect of a 10min infusion of Compound 1 at different doses (0.125, 0.25, 0.5, 1 and 2mg/kg/min) in the rat CHI model indicate that during treatment Compound1 invokes a sustained dose-dependent decrease of ICP (FIG. 1). Startingat 1 mg/kg/min Compound 1 yields a statistically significant largerreduction in ICP than in the solvent-treated group. In the 10 min periodfollowing the infusion a highly significant dose-dependent effect on ICPremains present (FIG. 2).

Effects of Compound 2. Compound 1 and Racemate (Comp. 1 and Comp. 2) onBrain Hemoglobin Concentration and Oxygenation.

Near-infrared spectroscopy (NIRS) of the rat brain ‘in vivo’ allows toquantify non-invasively saturation of brain haemoglobin with oxygen(HbSat) and total brain haemoglobin concentration ([HbTot]). The latteris a measure for cerebral blood volume (CBV). Changes in the redox stateof the mitochondrial enzyme cytochrome oxidase (CytOx), an indicator fortissue oxygenation, can also be monitored.

All compounds 2, 1 and the racemate (Comp. 1 and Comp. 2) do not have asignificant effect on [HbTot] when given 24 h after moderate head injuryat a i.v. dose of 0.5 mg/kg.min during 10 min, followed by 0.1 mg/kg.minduring 45 min. Only compound 2 induces a small but statisticallysignificant reduction of HbSat. HbSat is not affected by compound 1 andthe racemate (Comp. 1 and Comp. 2). At the applied dose all compounds donot have an effect on the redox state of CytOx. These results indicatethat in the applied experimental conditions a vasoconstrictive effect oncerebral blood vessels, if present, is limited and tissue oxygenation isnot jeopardised.

Influence of Anaesthesia on the Effects of Compound 2

The effects of treatment with Compound 2 (i.v. infusion at a dose of 0.1mg/kg.min during 30 min) at 24 h after moderate trauma were studiedusing different anesthetics (isoflurane, chloralhydrate, pentobarbital).When chloralhydrate (400 mg/kg i.p) is used as anesthetic, ICP decreasesto 75% of initial value and MABP gradually increases to 110% of initialvalue (medians, n=6). These effects are comparable with those observedunder isoflurane anesthesia. When pentobarbital (60 mg/kg i.p.) is used,Compound 2 induces a significant gradual increase in MABP up to 141% ofinitial value at the end of the infusion, whereas ICP decreases to 64%of initial value (medians, n=6). These results indicate that the samepattern of effects on ICP and MABP are observed under various types ofanesthesia. The fact that the compound reduces the ICP significantlyunder pentobarbital anesthesia is important, as barbiturates are oftenapplied in traumatic brain injury patients. Barbiturates also reduce theICP and an important additional effect can be obtained with thecompound.

The Effect of Repeated Application of Compound 1 and of Mannitol onElevated ICP in Traumatized Rats.

Compound 1 was given 2 times with intermittent periods of 20 min at ai.v. dose of 1 mg/kg/min during 10 min, starting a first time 20 minafter induction of severe head injury.

Mannitol was given i.v. in the same time windows as Compound 1 at a doseof 0.125 g/kg/min. The control animals received the solvent (containing10% HP-β-CD, pH 4) only.

Infusion with Compound 1 results in rapid reduction of ICP (FIG. 3).This effect is amplified after termination of each infusion period.Blood pressure drops during Compound 1 treatment but is restored againafter this episode. This is in contrast with mannitol, that induces alowering of ICP and an increase in blood pressure during each infusionfollowed by a decrease in blood pressure after termination of eachtreatment. Only in the Compound 1—treated animals a clear dissociationbetween the changes in blood pressure and ICP can be observed. Incontrast, the mannitol treated animals exhibit more or less parallelchanges in blood pressure and intracranial pressure. This indicates thatthe pharmacological effect of Compound 1 is different from that ofmannitol.

Effect of Compound 1 on Cold Lesion-Induced Rise of ICP in Rabbits

Cryo-lesions were induced in adult rabbits to obtain a pathological ICPthat is caused by tissue oedema. A 8 mm stainless steel rod was placedat predetermined coordinates on the exposed skull of deeplyanaesthetised rabbits and cooled for 10 min with liquid nitrogen. Oneday later the animals were re-anaesthetised and ICP and blood pressurecontinuously recorded as described for the rat. After a stabilisationperiod of 15 min, Compound 1 was infused for 10 min at a dose of 2mg/kg/min. Solvent (preclinical formulation containing 10% HP-β-CD, pH4) was given for 10 min at a rate of 2 ml/min.

During infusion of the Compound 1, the blood pressure drops and althoughthere is no immediate decrease in ICP, the ICP rise that is observed inthe solvent-treated animals tends to be antagonised (FIG. 4). When druginfusion is terminated, blood pressure comes back to the initial valueand a significant ICP reduction is seen that persists during the entirerecording period.

These results indicate that the compound reduces the ICP also innon-rodent species and in pathologic conditions different from closedhead injury.

The Effect of Compound 1 and on ICP in Non-Traumatized Animals.

Rats The effect of Compound 2, Compound 1 and Racemate (comp. 1 andcomp. 2) on ICP, MABP and CPP was tested in anaesthetisednon-traumatised rats. The compounds were administered i.v. and the samedose was given as in traumatized rats (0.5 mg/kg/min during 10 minutes,followed by 0.1 mg/kg/min during 50 min). The results were comparablewith those obtained in the traumatized animals.Conclusion

The results obtained in traumatized animals, animals with cold lesion,and non-traumatized animals indicate that the compounds are active invarious conditions, even in normal conditions. Their field ofapplication probably includes various pathological conditions in whichintracranial hypertension is present.

1. A compound according to Formula (I)

the pharmaceutically acceptable acid or base addition salts thereof, thestereochemically isomeric forms thereof and the N-oxide form thereof,wherein: m is 1 or 2; n is 0 or 1; m+n must equal 2 a, b, cindependently are a single or a double bond; X is a covalent bond or abivalent radical of a C₁₋₆ alkanediyl wherein one or more —CH₂—groupsmay be optionally replaced with —O—, —S—, —CO—, or NR⁷ — wherein: R⁷ ishydrogen, alkyl, Ar, Ar-alkyl, Het, Het-alkyl, hydroxyalkyl, alkyloxy,alkyloxyalkyl, alkyloxyalkyloxyalkyl, aminoalkyl, mono- ordialkylaminoalkyl, formyl, alkylcarbonylaminoalkyl,alkylcarbonyloxyalkyl, alkyloxycarbonyl, alkyloxycarbonylalkyl,alkylaminocarbonyl, alkylaminocarbonylalkyl, hydroxyalkyloxyalkyl,aminocarbonyl, aminocarbonylalkyl, alkyloxycarbonyl oralkylcarbonyloxyalkyloxyalkyl; Y is —CH₂—CH₂—, Z is N, in which case ais a double bond and b is a single bond or N—R⁷ in which case a is asingle bond, b is a double bond and R⁷ is defined as above; R¹, R²independently are hydrogen, hydroxy, alkyl, alkyloxy, Ar, Ar-alkyl,di(Ar-)alkyl, Het or Het-alkyl; —A—B- independently is a bivalentradical of formula—E—CR⁸═CR⁸—  (a-1);—CR⁸═CR⁸—E—  (a-2);—CR⁸═CR⁸—CR⁸═CR⁸—  (a-3); wherein R⁸ each independently is hydrogen,halo, hydroxy, alkyl or alkyloxy; E is a bivalent radical of formula—O—, —S—or—NR⁷- wherein R⁷ is defined as above; —C—D— independently is abivalent radical of formula—CR⁸═CR⁸—CR⁸═CR⁸—  (b-1);—N═CR⁸—CR⁸═CR⁸—  (b-2);—CR⁸═N—CR⁸═CR⁸—  (b-3);—CR⁸═CR⁸—N═CR⁸—  (b-4);—CR⁸═CR⁸—CR⁸═N—  (b-5); wherein R⁸ is defined as above; R³ is hydrogen,halo, hydroxy, alkyl, alkyloxy, Ar, Ar-alkyl, di(Ar-)alkyl, Het orHet-alkyl; R⁴ is hydrogen, alkyl, amino, alkylamino, Ar-amino,Het-amino, alkylcarbonylamino, Ar-carbonylamino, Het-carbonylamino,alkylaminocarbonylamino, Ar-aminocarbonylamino, Het-aminocarbonylamino,alkyloxyalkylamino, Ar-oxyalkylamino or Het-oxyalkylamino; R⁵ ishydrogen or alkyl; or R⁴ and R⁵ together may form a bivalent radical ofFormula—M—CR⁹═CR¹⁰—  (c-1);—CR¹⁰═CR⁹—M—  (c-2);—M—CR⁹R⁸—CR¹⁰R⁸—  (c3);—CR¹⁰R⁸—CR⁹R⁸—M—  (c-4);—CR⁸═N—NR⁷—  (c-5);—NR⁷—N═CR⁸—  (c-6);—CR⁸═CR⁹—CR¹⁰═CR⁸—  (c-7);—CR⁸R⁸—CR⁹R⁸—CR¹⁰R⁸—M—  (c-8);—M—CR¹⁰R⁸—CR⁹R⁸—CR⁸R⁸—  (c-9);—CR⁸R⁸—CR⁸═N—NR⁷—  (c-10);—NR⁷—N═CR⁸—CR⁸R⁸—  (c-11); wherein R⁷ and R⁸ are defined as above;R^(9,) R¹⁰ independently are hydrogen, alkyl, halo, haloalkyl; or R⁹ andR¹⁰ together may form a bivalent radical of formula —CR⁸═CR⁸—CR⁸═CR⁸—;and M is a bivalent radical of formula —CH₂—,—O—, —S— or —NR⁷— whereinR⁷ is defined as above; Ar is a homocycle selected from the group ofnaphthyl and phenyl, each optionally substituted with 1, 2 or 3substituents, each substituent independently selected from the group ofhydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl,haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl,aminocarbonyl and mono- or dialkylaminocarbonyl; Het is a monocyclicheterocycle selected from the group of pyrrolyl, pyrazolyl, imidazolyl,furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclicheterocycle selected from the group of quinolinyl, quinoxalinyl,indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzofuranyl and benzothienyl ; each monocyclic andbicyclic heterocycle may optionally be substituted on a carbon atom withhalo, hydroxy, alkyl or alkyloxy; alkyl is a straight or branchedsaturated hydrocarbon radical having from 1 to 6 carbon atoms; or is acyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms; oris a a cyclic saturated hydrocarbon radical having from 3 to 6 carbonatoms attached to a straight or branched saturated hydrocarbon radicalhaving from 1 to 6 carbon atoms; wherein each carbon atom can beoptionally substituted with halo, hydroxy, alkyloxy or oxo; halo is asubstituent selected from the group of fluoro, chloro, bromo and iodo;haloalkyl is a straight or branched saturated hydrocarbon radical havingfrom 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radicalhaving from 3 to 6 carbon atoms, wherein one or more of any member ofeither group of said carbon atoms are substituted with one or morehalo-atoms.
 2. A compound according to claim 1, characterized in that,independently of each other, Ar is a naphthyl or phenyl, each optionallysubstituted with 1 substituent, each substituent independently selectedfrom the group of halo or alkyl, Het is pyridinyl, pyrazinyl or indolyl,alkyl is methyl, ethyl or cyclohexylmethyl, halo is fluoro or chloro andhaloalkyl is trifluoromethyl.
 3. A compound according to claim 1,characterized in that —A—B—is a bivalent radical of formula (a-1) or(a-3), wherein E is a bivalent radical of formula - O, —S— or —NR⁷—wherein R⁷ is hydrogen, R⁸ is hydrogen, —C—D— is a bivalent radical offormula (b-1) or (b-2), wherein R⁸ is hydrogen and Y is a bivalentradical of formula CH₂—CH₂—.
 4. A compound according to claim 1characterized in that m and n are both
 1. 5. A compound according toclaim 1 characterized in that R¹ and R², each independently arehydrogen, alkyl, Ar-alkyl, Het or Het-alkyl.
 6. A compound according toclaim 1 characterized in that X is a bivalent radical of formula—CH₂CH₂— or —CH₂CH₂CH₂—.
 7. A compound according to claim 1characterized in that R³ is hydrogen or alkyl, Z is N—R⁷ wherein R⁷ ishydrogen or alkyl, a is a single bond and b is a double bond, and R⁴ andR⁵ together form a bivalent radical of Formula (c-1), (c-3), (c-5),(c-7), (c-8) or (c-10) wherein R⁷ and R⁸ are hydrogen.
 8. A compoundaccording to claim 7 characterized in that R⁹ and R¹⁰ together form abivalent radical of formula -CR⁸═CR⁸-CR⁸═CR⁸- wherein R is hydrogen.